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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Steroid hormones mediate sex difference in brain levels of tacrine and its hypothermic effect in the rat.

Tacrine, a reversible cholinesterase (ChE) inhibitor, lowers body temperature by increasing cholinergic activity in the hypothalamus. Its hypothermic effect was significantly greater in female than in male rats at doses of 2.5-12.5 mg/kg. Gonadectomy increased the maximum fall in temperature after tacrine (5 mg/kg) from 1.92+/-0.16 to 2.59+/-0.13 degrees C in males and from 2.96+/-0.25 to 3.63+/-0.27 degrees C in females. Testosterone (10 mg/rat) rats significantly reduced the hypothermia in gonadectomised males and females and abolished the gender difference. Adrenalectomy increased the fall in temperature after tacrine (5 mg/kg) to 2.92+/-0.15 degrees C in males and 4.18+/-0.24 degrees C in females. The sex difference that remained was abolished by four daily injections of corticosterone (5 mg/kg). Plasma ChE can bind tacrine thereby lowering the amount available to the brain. Ovariectomy decreased plasma ChE activity from 2.27+/-0.24 to 1.66+/-0.14, while adrenalectomy reduced it to 1.30+/-0.10 (micromoles acetylthiocholine hydrolysed/ml/h). This enzyme activity was unaffected by gonadectomy and adrenalectomy in males. Brain levels of tacrine, (5 mg/kg), 1 h after injection were 2.41+/-0.35 microg/gm in males and 4.97+/-0.57 microg/gm in females. Gonadectomy increased brain levels in males to 4.05+/-0.51 microg/gm and testosterone restored them to 2.64+/-0.3 microg/gm. The hypothermic effect of tacrine was highly correlated to its brain concentration after the hormonal manipulations. It is concluded that steroids can reduce the pharmacological effects of tacrine by interfering with its entry into the brain.[1]


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